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J. Med. Chem. 1996, 39, 2170-2177
Tyrphostins. 5. Potent Inhibitors of Platelet-Derived Growth Factor Receptor Tyrosine Kinase: Structure-Activity Relationships in Quinoxalines, Quinolines, and Indole Tyrphostins Aviv Gazit,† Harald App,‡ Gerald McMahon,‡ Jefferey Chen,‡ Alexander Levitzki,*,† and Frank D. Bohmer§ Department of Biological Chemistry, The Alexander Silverman Institute of Life Sciences, The Hebrew University of Jerusalem, Givat Ram, Jerusalem 91904, Israel, SUGEN, Inc., 515 Galveston Drive, Redwood City, California 94063-4720, and Max-Planck Society, Research Group “Growth Factor Signal Transduction” Medical Faculty, Friedrich-Schiller University, Drackendorfer Str. I D 07747, Germany Received October 3, 1995X
A series of 3-indoleacrylonitrile tyrphostins, 2-chloro-3-phenylquinolines, and 3-arylquinoxalines were prepared and tested for inhibition of platelet-derived growth factor receptor tyrosine kinase (PDGF-RTK) activity. The potency of the inhibitors was found to be quinoxalines > quinolines > indoles. Lipophilic groups (methyl, methoxy) in the 6 and 7 positions and phenyl at the 3 position of quinoxalines and quinolines were essential for potency, in contrast to the hydrophilic catechol group in tyrphostins active against EGFR kinase inhibition at different sites. The inhibitors showed selectivity for PDGF and were not active against EGF receptor and HER2/c-ErbB-2 receptor. Introduction Platelet-derived growth factor (PDGF) is a potent mitogen and mitogen for mesenchymal cells (for a recent review, see ref 1). The PDGF AA, AB, and BB isoforms interact differentially with PDGF R- and β-receptors. Both PDGF receptor types are closely related transmembrane tyrosine kinases whose activation by ligand binding is essential for cellular signaling. PDGF and its receptors have been shown to be involved in regulation of vital aspects of embryogenesis.2,3 In the adult, most of the proposed functions of PDGF relate to different responses to injury as wound healing and inflammation.4,5 PDGF-induced cell proliferation is also likely to be involved in a number of pathophysiological conditions such as atherosclerosis, restenosis,6 and fibrosis as well as in certain cancers such as gliomas. In atherosclerosis and restenosis, it is believed that PDGF, which is secreted by the injured wall of the blood vessel, induces the proliferation and migration of smooth muscle cells from the media to form the neointima.6 For various cancers it has been shown that the tumor cells express functional PDGF and PDGF receptors, suggesting that this autocrine loop may contribute to tumor growth.7 Indeed, interference with PDGF signaling led, in various tumor cell lines expressing PDGF and PDGFR, to growth inhibition and reversion of the transformed phenotype.8,9 Also, PDGF expression level has been found to correlate with malignancy in a number of human tumors.10-15 We and others have reported on the biological effects of PDGF tyrosine kinase blockers from the benzenemalononitrile family,16 indole-containing blockers,17 quinoline blockers,18,19 quinoxaline blockers,20,21 and aminopyrimidine blockers.22 In this article we report on the properties of indole, quinoline, and a large number * Address correspondence to this author. Tel: 972-2-585 404. Fax: 972-2-512 958. E-mail:
[email protected]. † The Hebrew University of Jerusalem. ‡ SUGEN, Inc. § Friedrich-Schiller University. X Abstract published in Advance ACS Abstracts, April 1, 1996.
S0022-2623(95)00727-8 CCC: $12.00
of quinoxaline compounds and on structure-activity relationships (SAR) which are important for inhibition of the PDGF receptor tyrosine kinase. Chemistry The tyrphostins of Table 1 were prepared by Knoevenagel condensation of the 3- or 5-formylindole with substituted acetonitriles. The quinolines II in Table 2 were prepared by Vilsmeyer reaction of amides I:23
Quinolines 18 and 19 were obtained by condensation of 3,4-dimethoxyaniline with the substituted β-chloroacrolein (ref 24). Quinoxalines were synthesized mostly by condensation of the appropriate 1,2-diamino aromatics with the 1,2-keto aldehyde or diketo compounds. Several quinoxalines were prepared by exchange reaction of the bis-thiosemicarbazones25 and condensation with 1,2-phenylenediamine. Results and SAR Our goal was to find inhibitors which would be both potent and selective as blockers of the PDGF receptor (PDGFR). Tyrphostins such as compound 1 and its analogs containing a catechol ring were moderately potent against PDGFR but not selective (Table 1). Tyrphostins 2-4, in which a 5-indole ring was introduced instead of a catechol ring, were either of low potency (2), not selective (4), or even more potent © 1996 American Chemical Society
Potent Inhibitors of PDGFR Tyrosine Kinase Table 1. Indole-Containing Tyrosine Kinase Inhibitors
Journal of Medicinal Chemistry, 1996, Vol. 39, No. 11 2171 Table 2. Quinoline-Containing Tyrosine Kinase Inhibitors
_R
a Determined as in Table 1. IC 50 values from a representative experiment. IC50 values are reproducible within
